2.3. Effects of SCFAs on Controlling Inflammation
SCFAs are the ligands for G protein-coupled receptors (GPCRs), which contain GPR43, GPR41, and GPR109A, that trigger anti-inflammatory signaling cascades
[34]. SCFAs also modulate immune responses, partially by affecting gene expressions and the epigenome through the inhibition of histone deacetylases (HDAC)
[35][36]. SCFAs are saturated aliphatic organic acids that comprise one to six carbon atoms, of which propionate, acetate, and butyrate are the most abundant and are produced by anaerobic fermentation of dietary fiber in the gut
[37]. Firmicutes (gram-positive) and Bacteroidetes (gram-negative) are the most abundant phyla in the intestines, with members of Firmicutes mainly producing butyrate, whereas acetate and propionate are the primary metabolic end products of members of Bacteroidetes
[38]. SCFA butyrate protects intestinal epithelial cells and stabilizes hypoxia-induced factors and, thus, attenuates local and systemic inflammation
[39]. Dietary-derived butyrate inhibits innate lymphoid cells and subsequently reduces lung inflammation, airway hyperreactivity, and eosinophilia in an allergic asthma murine model
[40]. SCFAs can reduce impairments of the intestinal epithelial barrier due to their protection against high-fructose-diet-induced neuroinflammation
[41]. Clinical studies have revealed that daily oral supplementation of 10
10 of
Akkermansia muciniphila bacteria (live or pasteurized) can improve insulin sensitivity and reduce insulinemia and plasma total cholesterol in overweight or obese insulin-resistant volunteers relative to a placebo. After 3 months of supplementation,
Akkermansia muciniphila reduced the levels of the relevant blood markers for liver dysfunction and inflammation
[42]. The butyrate–GPR109A axis inhibited LPS-induced NF-κB activation in colonic cell lines and in the colon of mice
[43]. SCFAs, as an HDAC inhibitor, can protect the intestinal barrier from disruption by inhibiting the LPS–NLRP3 inflammasome axis
[44]. Acetate diminishes NLRP3 inflammasome activation through GPR43 and Ca
2+-dependent mechanisms, which underscores the mechanism of metabolite-attenuated NLRP3 inflammasome activity that mitigates CVD development
[45]. As illustrated in
Figure 21, SCFA treatment can inhibit NF-κB/NLRP3 signaling, which may prevent inflammation-associated heart arrhythmia.
Figure 21. Effects of gut microbiota-derived endotoxin and metabolites on the regulation of NF-κB/NLRP3 inflammasome signaling. Gut microbiota-derived endotoxin or metabolite signaling (such as LPS/TLR4, TMAO, and SCFA/GPCRs) that altered down-stream NF-κB/NLRP3 inflammasome signaling and their effects on cardiac physiology. LPS/TLR4 and TMAO activates NF-κB/NLRP3 axis and induces secretion of IL-1β/IL-18. However, SCFA/GPCRs signaling inhibit NF-κB/NLRP3 signaling. LPS: lipopolysaccharide, TLR4: toll-like receptor 4, TMAO: trimethylamine-N-oxide, SCFA: short-chain fatty acid, GPCRs: G-protein coupled receptors, ROS: Reactive oxygen species, NLRP3: NLR family pyrin domain containing 3, ASC: apoptosis-associated speck-like protein containing a caspase recruitment domain, Pro-IL-1β: Pro-form interleukin 1 beta, Pro-IL-18: pro form interleukin 18, IL-1β: interleukin 1 beta, IL-18: interleukin 18.
2.4. HDACs’ Inhibition of Cardiac Inflammation
SCFA exerts its beneficial effects by inhibiting inflammation through the activation of GPR41/43 signaling and reduction in HDAC levels
[46]. HDACs play key roles in the progression of CVDs and contribute to AF generation
[47]. Inhibition HDACs was recommended as a novel therapeutic strategy for cardiac arrhythmia and AF
[47][48]. HDAC11 was significantly overexpressed in both human and mouse diabetic HF hearts
[49]. Knockout of HDAC11 improved dyslipidemia and reduced inflammation in the heart of mice fed with fructose when compared with controls
[49]. The HDAC inhibitor (HDACi) recovers cardiac function by reducing the expression of inflammatory cytokines and by ameliorating inflammatory cell infiltration in the heart
[50]. Our previous laboratory results indicated that HDACi (MPT0E014 or MS-275) treatments ameliorated TNF-α-induced mitochondrial dysfunction with increased mitochondrial superoxide production and decreased ATP synthesis in atrial cardiomyocytes
[51]. MPT0E014-treated pulmonary vein cardiomyocytes had reduced calcium transient amplitudes, sodium-calcium exchanger currents, and the expression of ryanodine receptor
[52]. Additionally, MPT0E014-treated rabbits had less AF and shorter AF duration in AF-rabbit model (with rapid atrial pacing and acetylcholine infusion) rabbit model than controls
[52]. Moreover, MS-275 ameliorated hyperglycemia, insulin resistance, TNF-α expression, and stress signaling in skeletal muscle in high fat high fructose-fed mice
[53]. Therefore, HDACi treatment is a potential strategy for suppressing cardiac arrhythmogenesis.